Substituted 3-(benzoylureido) thiophene derivatives, processes for preparing them and their use

1. A compound of formula I

wherein

R5 is F, Cl or Br;

R1 is H, F, Cl or Br;

R2 is CF 3 , OCF 3 , NO 2 , O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, COOH, CONH 2 , CONH(C 1 –C 6 )-alkyl, CON((C 1 –C 6 )-alkyl) 2 , SO 2 —(C 1 –C 6 )-alkyl, or the A radical;

R3 is H, (C 1 –C 6 )-alkyl, COO(C 1 –C 6 )-alkyl, SO 2 —(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkyl-phenyl, phenyl, SO 2 -phenyl, wherein the phenyl rings of said (C 1 –C 6 )-alkyl-phenyl, phenyl and SO 2 -phenyl groups are optionally mono- or disubstituted by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 –C 6 )-alkyl or CONH 2 ;

R4 is H, (C 1 –C 6 )-alkyl, COO(C 1 –C 6 )-alkyl, SO 2 —(C 1 –C 6 )-alkyl, SO 2 -piperidinyl, SO 2 -piperazinyl, (C 1 –C 6 )-alkylphenyl,

wherein said SO 2 -piperidinyl and SO 2 -piperazinyl groups and the phenyl ring of said (C 1 –C 6 )-alkylphenyl group are optionally mono- or disubstituted by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 –C 6 )-alkyl or CONH 2 ;

A is a heterocyclic radical of the formula 2a, 2b, 2c or 3;

X is O or NH;

Y is OH or NH 2 ;

Z is OH, O(C 1 –C 6 )-alkyl, NH 2 , NH(C 1 –C 6 )-alkyl or N((C 1 –C 6 )-alkyl) 2 ;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein

R5 is F, Cl or Br;

R1 is H or F;

R2 is CF 3 , OCF 3 , NO 2 , O—(C 1 –C 6 )-alkyl, CO(C 1 –C 6 )-alkyl, COOH, CONH 2 , CONH(C 1 –C 6 )-alkyl, CON((C 1 –C 6 )-alkyl) 2 , SO 2 —(C 1 –C 6 )-alkyl, or the A radical;

R3 is H, (C 1 –C 6 )-alkyl, COO(C 1 –C 6 )-alkyl, SO 2 (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylphenyl, phenyl, SO 2 -phenyl, wherein the phenyl rings of said (C 1 –C 6 )-alkylphenyl, phenyl and SO 2 -phenyl groups are optionally mono- or disubstituted by F or Cl;

R4 is H, (C 1 –C 6 )-alkyl, COO(C 1 –C 6 )-alkyl, SO 2 —(C 1 –C 6 )-alkyl, SO 2 -piperidinyl, SO 2 -piperazinyl, (C 1 –C 6 )-alkylphenyl,

wherein said SO 2 -piperidinyl and SO 2 -piperazinyl groups and the phenyl ring of said (C 1 –C 6 )-alkylphenyl group are optionally mono- or disubstituted by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 –C 6 )-alkyl or CONH 2 ;

A is a heterocyclic radical of the formula 2a, 2b or 2c;

X is O or NH;

Y is OH or NH 2 ;

Z is OH;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 , wherein

R5 is F;

R1 is F;

R2 is COOH, CONH 2 , CONH(C 1 –C 6 )-alkyl, CON((C 1 –C 6 )-alkyl) 2 , or the A radical;

R3 is H, (C 1 –C 6 )-alkyl, COO(C 1 –C 6 )-alkyl, SO 2 (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkyl-phenyl, phenyl, SO 2 -phenyl,

wherein the phenyl rings of said (C 1 –C 6 )-alkylphenyl, phenyl and SO 2 -phenyl groups are optionally mono- or disubstituted by F;

R4 is H, (C 1 –C 6 )-alkyl, COO(C 1 –C 6 )-alkyl, SO 2 —(C 1 –C 6 )-alkyl, SO 2 -piperidinyl, SO 2 -piperazinyl, (C 1 –C 6 )-alkylphenyl,

wherein said SO 2 -piperidinyl and SO 2 -piperazinyl groups and the phenyl ring of said (C 1 –C 6 )-alkylphenyl group are optionally mono- or disubstituted by by F or (C 1 –C 6 )-alkyl;

A is a heterocyclic radical of the formula 2a or 2b;

X is O or NH;

Y is OH or NH 2 ;

and pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4 further comprising one or more additional active ingredients.

6. The pharmaceutical composition of claim 5 wherein said additional active ingredient is selected from the group consisting of antidiabetics, hypoglycemic active ingredients, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients acting on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists or amphetamines.

7. A method of reducing blood sugar comprising administering to a patient in need thereof a compound of claim 1 .

8. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1 .

9. A method of treating lipid and carbohydrate metabolism disorders comprising administering to a patient in need thereof a compound of claim 1 .

10. A method of treating arteriosclerotic symptoms comprising administering to a patient in need thereof a compound of claim 1 .

11. A method of treating insulin resistance comprising administering to a patient in need thereof a compound of claim 1 .

12. A process for preparing a compound of claim 1 , which comprises reacting ureas of the formula 5 with benzoic acid derivatives of the formula 4

wherein R1 to R5 are each as defined in formula I of claim 1 and X1 is Cl.

13. A process for preparing a compound of claim 1 , which comprises reacting 3-aminothiophene derivatives of the formula 6 with a benzoic acid derivative of the formula 4

wherein R1 to R5 are each as defined in formula I of claim 1 and X1 is NCO.